“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society , copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request authordirected link to Published Work, see https://pubs.acs.org/doi/pdf/10.1021/jacs.6b10351

Alkyl Bromides as Mild Sources in Ni-Catalyzed Hydroam- idation of with Isocyanates Xueqiang Wang,† Masaki Nakajima,†‡ Eloisa Serrano†‡ and Ruben Martin†§* †Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Cata- lans 16, 43007 Tarragona, Spain § ICREA, Passeig Lluïs Companys, 23, 08010, Barcelona, Spain Supporting Information Placeholder

ABSTRACT: A catalytic hydroamidation of alkynes with Prompted by the utmost synthetic relevance of acryla- 3 isocyanates using alkyl bromides as hydride sources has mides in pharmaceuticals, agrochemicals and polymers, been developed. The method turns parasitic b-hydride we wondered whether it would be possible to design a elimination into a strategic advantage, rapidly affording catalytic hydroamidation of alkynes by intercepting the acrylamides with excellent chemo- and regioselectivity. in situ generated alkenyl metal species with isocyanates, privileged synthons in both industrial and academic 4,5 Hydrometalation of alkynes ranks among the most fun- laboratories. At the outset of our investigations, how- damental reactions in , ena- ever, it was unclear whether such protocol could ever be bling a rapid access to well-defined alkenyl metal spe- implemented, as isocyanates have rarely been employed cies.1 At present, intermolecular C–C bond-forming in catalytic endeavors other than cycloaddition events 6,7 reactions via catalytic hydrofunctionalization of alkynes (Scheme 1, path b). This is likely due to their excep- remains confined to the utilization of well-defined metal tional sensitivity to both and proton sources as hydride species or the presence of acids as well as their strong binding properties to low valent 8,9 donors (Scheme 1, path a).1,2 Unfortunately, these condi- metal species. We anticipated that a mild generation of tions preclude the use of partners sensitive to either met- the transient metal hydride would be critical for suc- 10 al hydrides or acidic media. If successful, a new design cess. To such end, we questioned whether we could principle capable of expanding the boundaries of turn b-hydride elimination, traditionally considered a hydrofunctionalization for C–C bond-formation by using drawback when coupling unactivated alkyl halides,11 unconventional hydride sources could lead to new into a strategic advantage, thus offering a novel method knowledge in our ever-growing organometallic arsenal. capable of delivering metal hydrides under mild condi- tions while releasing volatile byproducts (Scheme 1, Scheme 1. Alkyne Hydrofunctionalization and Isocyanates. bottom).12 As part of our interest in heterocu- 13,7a-b "Classical" C–C bond-formation via catalytic hydrometalation mulenes, we report herein the successful realization of this new design principle, accessing a wide range of catalyst + H C [M]–H or H [M]-H or H+ required acrylamides in a both chemo- and regioselective manner. + C [M]=B,Si,Zr,Sn,.. ample precedents Table 1. Optimization of the Reaction Conditions.a path a RNCO in catalytic endeavors H limited use in catalysis catalyst N R di(tri)merization RNCO + RNCO path b sensitive to [M]–H or H+ privileged O carbonyl synthons This work: hydroamidation with RNCO & alkylBr as hydride source

mild & catalytic O R1 Br Ni-H generation Ni H H N H Ni + RNCO H β-hydride β-H elimination as elimination volatile strategic advantage chemo & byproducts regioselective Ph Ph NiBr2·diglyme (10 mol%) O NiBr2·diglyme (10 mol %) O 1a L4 (20 mol %) H NHt-Bu L4 (20 mol %) H NHR2 + R1 Ar + R2NCO Mn, i-PrBr (1.50 equiv) Mn, i-PrBr (1.50 equiv) Ph Ph R1 Ar t-BuNCO (2a) NMP, rt 1a-p 2 3a-p 3a NMP, rt Entry Deviation from standard conditions 2a (%)b O 1 None 91c (83d) H NHt-Bu R = H, 91% (3a) 2 L1 instead of L4 0 R = OPiv, 75% (3b) 3 L2 instead of L4 45 N N R = Cl, 76% (3c) 4 R R L3 instead of L4 0 R=H (L1) R = F, 87% (3d) 3a 5 L5 instead of L4 64 R=Me (L2) R O R O O 6 L6 instead of L4 66 H NHt-Bu H NHt-Bu H NHt-Bu R2 R2 2 7 PPh3 instead of L4 38 R R1 8 Ni(COD)2 as catalyst 68 R R R 9 t-BuBr as hydride source 69 N N 10 DMF (DMA) instead of NMP 73 (54) R1 R1 R = Me, 91% (3e) R1 = t-Bu; R2 = H, 50% (3g)c R = F, 88% (3i)d 1 2 11 Zn instead of Mn 54 R = CF3, 64% (3f) R = Cp; R = Ph, 81% (3h) R = H, 92% (3j) R1=R2=H (L3) 12 Me(EtO) SiH (H ) as hydride source 17e (0) O 2 2 R1=Me; R2=Ph (L4) O O 13 NaBH (t-BuOH) as hydride source 0 (0) H NHt-Bu 4 R1=n-Bu; R2=Ph (L5) H NHR H NHt-Bu 14 No NiBr ·diglyme, no L5 or no Mn 0 2 R1=n-Bu; R2=Me (L6) i-Pr Ph Ph R1 R2 a 1 2 h,i 1a (0.25 mmol), 2a (0.38 mmol), NiBr2·diglyme (10 R = Cp', 95% (3m) R = R = n-Pr, 57% (3q) R R = i-Pr, 93% (3n) R1 = t-Bu; R2 = Me, 38% (3r) mol%), L4 (20 mol%), Mn (0.38 mmol), NMP (0.25 M) at e f b R = OCF3, 64% (3k) R = Cy, 85% (3o) rt, 12 h. HPLC yields using naphthalene as internal stand- R = OTs, 97% (3l)d R = H, 89% (3p)g c d e ard. Isolated yield. NiBr2·diglyme (5 mol%), 24 h. a b Na2CO3 (0.75 mmol), no Mn, E:Z = 5:1. As Table 1 (entry 1), at 0.50 mmol scale. Isolated yields, average of at least two independent runs. c 35 ºC, 72 h. d E/Z We started our proposed protocol by evaluating the hy- = 14:1. e E/Z = 15:1. f E/Z = 13:1. g Subsequent TFA treat- droamidation of 1a with 2a (Table 1), as the t-butyl ment at reflux. h Using neocuproine (20 mol%) as ligand at group in acrylamides could be used as a vehicle for fur- 10 ºC. i E/Z = 6:1. Cp = cyclopropyl, Cp’ = cyclopentyl. ther functionalization.14 After careful optimization,15 we found that a combination of NiBr2·diglyme, L4, Mn as With an optimized set of conditions in hand, we turned reducing agent in NMP at rt, and using simple i-PrBr as our attention to validate the generality of our hydroami- the hydride source provided the best results, resulting in dation protocol. As illustrated in Table 2, a host of dif- 91% isolated yield of 3a as a single diastereoisomer ferent alkyl- or aryl-substituted symmetrical or unsym- metrical acetylenes could participate well in the targeted (entry 1). In line with our expectations, subtle modifica- 16 tions on the ligand backbone led to profound changes on reaction. Notably, similar results were obtained regard- the reaction outcome, with ortho-substituted 1,10- less of the electronic and steric parameters of the sub- phenanthroline ligands being considerably more reactive stituents on the alkyne terminus. In all cases, a single than bipyridine motifs (entries 2-6), suggesting that a regioisomer with high levels of diastereoselectivity was reasonable steric bulk was critical for stabilizing the obtained, with the amide function located adjacent to the transient reaction species. Likewise, other Ni sources, aromatic motif, an observation corroborated by X-ray 15 solvents, reducing agents, or related alkyl bromides as crystallography (3a, 3l). Particularly interesting was hydride sources resulted in lower yields (entries 7-11).15 the ability to accommodate aryl halides (3c, 3d, 3i), As expected, classical hydrometalation techniques based pivalates (3b) or tosylates (3l), as these motifs have on R SiH, H , NaBH or alcohols as protic sources re- successfully been used as counterparts in Ni-catalyzed 3 2 4 17 sulted in the degradation of 2a, with little of 3a, if any, cross-coupling reactions, thus providing an additional being observed in the crude mixtures (entries 12-13). handle for further derivatization. Notably, the coupling Notably, only traces of a reductive amidation of i-PrBr of isocyanates other than 2a posed no problems, and were observed, thus showing the unique features of our 3m-3o could all be prepared in high yields. Upon simple 15 method.7a Control experiments in the absence of Ni exposure to TFA, we found that primary amides could catalyst, L4, i-PrBr or Mn revealed that all these param- be within reach (3p), thus effectively using the t-butyl eters were necessary for the reaction to occur (entry 14). group as a masked form of hydrogen while leading to a priori inaccessible building blocks via classical alkyne Table 2. Scope of Aryl- & Alkyl-Substituted Acetylenes.a,b hydroamidation processes.1,5 Importantly, the hydroami- dation could also be applied to aliphatic internal alkynes (3q, 3r), albeit in slightly lower yields. Table 3. Scope of Silyl- & Boryl-Substituted Acetylenes.a,b

O O NiBr2·diglyme (10 mol %) beyond reach otherwise with such a high regioselectivity L4 (20 mol %) H NHR2 H NHR2 R via classical hydroamidation of alkynes posessing two Mn, i-PrBr (1.50 equiv) or 1,5,21 4a-r R R different aromatic residues without steric bias. R2NCO, NMP, rt =[Si],[B] 5a-r 5a'-r' O O Scheme 2. Synthetic Applicability H NHt-Bu H NHt-Bu O O O O H NHt-Bu O O B t-Bu Si H NHt-Bu Me Me Et3Si Ph N Me3Si Ph 5d Me 55% (5a) 79% (5b) O 88% (5c) O 99% NaH, MeI O R = H, 92% (5d) H NHt-Bu R = OPiv, 80% (5e) O t-Bu R = OTs, 99% (5f) O t-Bu O t-Bu H N NIS H N NCS H N Me3Si R = OMe, 76% (5g) Me Me Me R = BPin, 63% (5h) 93% 84% I Ph 7 Me3Si Ph 6 Cl Ph 8 R = CO2Me, 70% (5i) R R = F, 84% (5j) 5e (1) NIS 81% (2) Pd(PPh ) (10 mol%) O O Me 3 4 Me ArB(OH)2, K2CO3, 90 ºC H NHt-Bu H NHR O H NH Ar = OMe O t-Bu Me3Si S Me3Si Ph Me H N R = i-Pr, 60% (5l) Me3Si Ph Me Ar Ph 55% (5k) R = Cy, 61% (5m) 76% (5o) 9 R = 2-OMeC H , 65% (5n) 6 4 O O O H NHt-Bu Next, we decided to perform deuterium-labeling H NHt-Bu t-BuHN H experiments to gather evidence about the mechanism of H Me3Si Me3Si our Ni-catalyzed hydroamidation protocol (Scheme 3, top pathway). As shown, 3a-D was prepared in high c d 58% (5p) 55% (5q') 73% (5r) OMe yields from either (CD3)2CHBr or (CH3)2CDBr with a b 75% and 15%-D content, respectively, suggesting that a As Table 1 (entry 1), at 0.50 mmol scale. Isolated yields, c d b-hydride elimination/migratory insertion might occur at average of two independent runs. E/Z = 1.8:1. Using 1r 22 followed by TBAF (1.20 equiv). some extent prior to alkyne binding. The stoichiomeric experiments with Ni(L4)2 are particularly illustrative Encouraged by these results, we questioned whether we (Scheme 3, bottom);23 specifically, we found that 3a was could extend the scope of our protocol to silyl- or boryl- solely obtained in the presence of i-PrBr, thus ruling out substituted acetylenes, as these motifs have shown to be an oxidative cyclization of Ni(0), 1a and 2a en route to 18 versatile intermediates in organic synthesis. As shown I.6 Although further studies are needed, we currently in Table 3, this turned out to be the case. As for the propose a pathway consisting of a hydrometalation with results compiled in Table 2, the amide function in 5a-5p in situ generated Ni(II)-hydride, single electron transfer was invariably located adjacent to the aromatic or (SET) mediated by Mn en route to a Ni(I) intermediate24 vinylic motif, an assumption that was confirmed by X- followed by RNCO insertion25 and a final SET to ray crystallography (5e). The absence of a p-component recover the Ni(0) species. At present, we cannot rule out on the alkyne terminus resulted in 5q’, a selectivity a RNCO insertion into vinyl-Ni(II) species or a switch that is attributed to the electropositivity of Si and comproportionation event to generate the corresponding 19 hyperconjugation into the adjacent Si–C s* orbital. As Ni(I) intermediates, as a non-negligible yield of 3a was shown for 5n, the reaction could be extended to aromatic obtained in the absence of Mn (Scheme 3, bottom).26 isocyanates with similar ease. Interestingly, desilylation with TBAF yielded 5r, thus accessing compounds that Scheme 3. Mechanistic Experiments. formally derive from a hydroamidation of free alkynes. As anticipated, the chemoselectivity posed no problems, as acetals (5b), esters (5i), aryl boronates (5h), heteroaromatics (5k), aryl fluorides (5j) or (5o, 5p) could perfectly be tolerated. As for Table 2, groups amenable for Ni-catalyzed C–O cleavage such as aryl pivalates (5e) or tosylates (5f) did not compete with the efficacy of our hydroamidation event.20 The usefulness of our synthetic method is illustrated in Scheme 2, by rapidly preparing synthetically relevant 7 and 8 in high yields by a N-alkylation/ipso-halogenation sequence.15 The versatility of our method is further highlighted by the synthesis of 9,15 accessing acrylamides that would be

Isotope-labelling studies (2) Trost, B. M. Chem, Eur. J. 1998, 4, 2405. Me CD3 (3) (a) Ekici, Ö. D.; Li, Z. Z.; Campbell, A. J.; James, K. E.; Br Br O D C Me O Asgian, J. L.; Mikolajczyk, J.; Salvesen, G. S.; Ganesan, R.; 3 H 1a D D NHt-Bu Ni / L4 Ni / L4 D NHt-Bu Jelakovic, S.; Grütter, M. G.; Powers, J. C. J. Med. Chem. + 2006, 49, 5728. (b) The Amide Linkage: Structural Signifi- Mn, NMP Mn, NMP Ph Ph t-BuNCO Ph Ph 3a-D 92% 92% 3a-D cance in Chemistry, Biochemistry and Materials Science 75% D-content 2a 15% D-content (Eds.: Greenberg, A.; Breneman, C. M.; Liebman, J. F.), Wiley-Interscience, New York, 2000. Ph Me Stoichiometric experiments Me Ph (4) (a) Pace, V.; Monticelli, S.; de la Vega-Hernandez, K.; N N Castoldi, L. Org. Biomol. Chem. 2016, 14, 7848. (b) Ulrich, Ni(L4)2 (1 equiv) Ni N H. In Chemistry and Technology of Isocyanates, Ed.; John Mn (X equiv), i-PrBr N Me Ph Wiley & Sons, New York, 1996. (c) Ozaki, S. Chem. Rev. X=0, 35%; X=1.5, 81% Ph Me Ni(L4)2 1972, 72, 457. 1a + 3a L4 (5) This technique will represent, conceptually aside, a power- 1 2a R Ni ful alternative to recent elegant hydrocarbamoylation tech- N R3 niques based on formamides that require rather specific sub- Ni(L4) (1 equiv) 2 R2 stitution patterns, and in most instances, harsh conditions. O I Mn (X equiv), no i-PrBr unlikely See: (a) Fujihara, T.; Katafuchi, Y.; Iwai, T.; Terao, J.; Tsuji, X=0 or X=1.5, 0% Y. J. Am. Chem. Soc. 2010, 132, 2094. (b) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, In summary, we have discovered a conceptually new and 5070. (c) Kobayashi, Y.; Kamisaki, H.; Yanada, K.; Yanada, mild hydroamidation of alkynes with isocyanates by R.; Takemoto, Y. Tetrahedron Lett. 2005, 46, 7549. For using in situ generated nickel hydrides from light bro- aminocarbonylation techniques performed at CO pressures: moalkanes, turning parasitic b-hydride elimination into a (d) Park, J. H.; Kim, S. Y.; Kim, S. M.; Chung, Y. K. Org. Lett. 2007, 9, 2465. (e) Brennführer, A.; Neumann, H.; Bel- strategic advantage. The method is characterized by its ler, M. ChemCatChem 2009, 1, 28, and references therein. generality and excellent chemo- & regioselectivity, sug- (6) For reviews on cycloaddition techniques using isocyanates: gesting that mechanistically distinct protocols could be (a) Thakur, A.; Louie, J. Acc. Chem. Res. 2015, 48, 2354. (b) initiated via b-hydride elimination. Further investiga- Perreault, S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149. tions along these lines are ongoing in our laboratories. (7) For selected catalytic techniques not involving cycloaddi- tion events: (a) Serrano, E.; Martin, R. Angew. Chem. Int. ASSOCIATED CONTENT Ed. 2016, 55, 11207. (b) Correa, A.; Martin, R. J. Am. Chem. Soc. 2014, 136, 7253 (c) Hsieh, J.-C.; Cheng, C.-H. Chem. Supporting Information. Experimental procedures and Commun. 2005, 4554. (e) Schleicher, K. D.; Jamison, T. F. spectral data. This material is available free of charge via Org. Lett. 2007, 9, 875. the Internet at http://pubs.acs.org. (8) For selected seminal stoichiometric studies of metal com- plexes with isocyanates, see: (a) Hoberg, H.; Guhl, D. J. AUTHOR INFORMATION Organomet. Chem. 1990, 384, C43. (b) Hernandez, E.; Hoberg, H. J. Organomet. Chem. 1987, 328, 403. (c) Corresponding Author Hoberg, H.; Summermann, K.; Milchereit, A. Angew. Chem., Int. Ed. Engl. 1985, 24, 325. (d) Villa, J.F.; Powell, * [email protected] H.B. Inorg. Chim. Acta 1979, 32, 199. Author contributions (9) Braunstein, P.; Nobel, D. Chem. Rev. 1989, 89, 1927. ‡ (10) For selected reviews on metal hydrides: (a) Eberhardt, N. A.; These authors contributed equally to this work Guan, H. Chem. Rev. 2016, 116, 8373. (b) Larionov, E.; Li, H.; Mazet, C. Chem. Commun. 2014, 50, 9816. Funding Sources (11) For selected reviews: (a) Hu, X. Chem. Sci. 2011, 2, 1867. No competing financial interests have been declared. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417. (c) Frisch, A. C.; Beller, M. Angew. Chem., Int. ACKNOWLEDGMENT Ed. 2005, 44, 674. (12) For elegant transfer hydrocyanations of p-systems initiated We thank ICIQ, the European Research Council (ERC- by b-hydride elimination: (a) Fang, X.; Yu, P.; Morandi, B. 277883), MINECO (CTQ2015-65496-R & Severo Ochoa Science 2016, 351, 832. (b) Bhawal, B. N.; Morandi, B. Excellence Accreditation 2014-2018, SEV-2013-0319) and ACS Catal. 2016, 6, 7528. (c) Fang, X.; Yu, P.; Cerai, G. P.; Cellex Foundation for support. Johnson Matthey, Umicore Morandi, B. Chem. Eur. –J. 2016, 22, 15629. and Nippon Chemical Industrial are acknowledged for a (13) For recent examples: (a) Börjesson, M.; Moragas, T.; Martin, R. J. Am. Chem. Soc. 2016, 138, 7504. (b) Moragas, T.; gift of metal & ligand sources. E. Serrano thanks MINECO Gaydou, M.; Martin, R. Angew. Chem. Int. Ed. 2016, 55, for a FPI fellowship. We sincerely thank E. Escudero and 5053. (c) Wang, X.; Nakajima, M.; Martin, R. J. Am. Chem. E. Martin for X-ray crystallographic data. Soc. 2015, 137, 8924. (d) Wang, X.; Liu, Y.; Martin, R. J. Am. Chem. Soc. 2015, 137, 6476. (e) Moragas, T.; Cornella, REFERENCES J.; Martin, R. J. Am. Chem. Soc. 2014, 136, 17702. (1) (a) Trost, B. M.; Ball, Z. T. Synthesis 2005, 6, 853. (b) (14) Bailey, P. D.; Mills, T. J.; Pettecrew, R.; Price, R. A. In Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, Comprehensive Organic Functional Groups Transformation 3079. (c) Comprehensive Organic Synthesis, Vol. 8. Reduc- II, Vol. 5, Eds.; A. R. Katritzky, R. J. K. Taylor, Elsevier, tion; Trost, B.; Fleming, I., Eds.; Pergamon: Oxford, 1991. Oxford, 2005, pp. 201 – 294. (15) See the Supporting Information for details.

(16) The mass balance accounts for semireduction of the alkyne. (22) 3a-D was obtained with complete D-incorporation when (17) For reviews dealing with Ni-catalyzed cross-coupling reac- (CD3)CDBr was used as hydride source. Notably, no D- tions: (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Na- incorporation was observed when using L4-d6 (see ref. 15). ture 2014, 509, 299. (b) Montgomery, J. Organonickel (23) Powers, D. C.; Anderson, B. L.; Nocera, D. G. J. Am. Chem. Chemistry. In Organometallics in Synthesis; Lipshutz, B. H., Soc. 2013, 135, 18876 – 18883. For an improved protocol of Ed.; Wiley; Hoboken, NJ, 2013; pp 319-428. (c) Rosen, B. Ni(0)(phenanthroline)2 complexes, see ref. 13b. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, (24) For the formation of intermediate Ni(I) species generated A.-M.; Garg, N. K. Percec, V. Chem. Rev. 2011, 111, 1346. from SET processes, see: (a) Laskowski, C. A.; Bungum, D. (18) (a) Hall, D. G. Boronic Acids-Preparation, Applications in J.; Baldwin, S. M.; Del Ciello, S. A.; Iluc, V. M.; Hillhouse, Organic Synthesis and Medicine; Hall, D. G., Ed.; Wiley- G. L. J. Am. Chem. Soc. 2013, 135, 18272. (b) Breitenfeld, VCH: Weinheim, Germany, 2005. (b) Coats, R. M.; Den- J.; Ruiz, J.; Wodrich, M. D.; Hu, X. J. Am. Chem. Soc. 2013, mark, S.; Handbook of Reagents for Organic Synthesis. Re- 135, 12004. (c) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. agents, Auxiliaries and Catalysts for C–C Bond Formation; 2013, 135, 16192. See also ref. 13. J. Wiley & Sons, Inc., New York, 1999. (25) Ni(I) species have been shown to rapidly react with hetero- (19) For seminal studies in hyperconjugation with organic cumulenes other than RNCO, see: Menges, F. S.; Craig, S. silanes: (a) Whitmore, F. C.; Sommer, L. H. J. Am. Chem. M.; Tçtsch, N.; Bloomfield, A.; Ghosh, S.; Krüger, H. –J.; Soc. 1946, 68, 481. (b) Sommer, L. H.; Whitmore, F. C. J. Johnson, M. A. Angew. Chem. Int. Ed. 2016, 55, 1282. Am. Chem. Soc. 1946, 68, 485. (26) For selected comproportionation events en route to Ni(I) (20) For selected reviews on Ni-catalyzed C–O cleavage: (a) species, see: (a) Cornella, J.; Gomez-Bengoa, E.; Martin, R. Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48, 1717. (b) J. Am. Chem. Soc. 2013, 135, 1997. (b) Velian, A.; Lin, S.; Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43, Miller, J. M.; Day, M. W.; Agapie, T. J. Am. Chem. Soc. 8081. (c) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. 2010, 132, 6296. (d) Jones, G. D.; Martin, J. L.; McFarland, Chem. 2013, 19. C.; Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.; (21) In line with this notion, the hydroamidation of 1-methoxy-4- Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. (phenylethynyl)benzene led to 1:1 regioisomeric mixtures. Am. Chem. Soc. 2006, 128, 13175.

O R1 Br Ni catalyst H N Ni H RNCO H H 40 examples up to 99% yield volatile byproducts Excellent chemo- and regioselectivity profile β-hydride elimination as strategic advantage Mild conditions & user-friendly